Retrograde signalling at the synapse: a role for Wnt proteins

2005 ◽  
Vol 33 (6) ◽  
pp. 1295-1298 ◽  
Author(s):  
P.C. Salinas
Keyword(s):  
Synapse Formation ◽  
Glycogen Synthase ◽  
Signalling Pathway ◽  
Axon Extension ◽  
Wnt Proteins ◽  
Retrograde Signalling ◽  
Synaptic Differentiation ◽  
The Central Nervous System ◽  
Gsk 3Β

The formation of functional synapses requires a proper dialogue between incoming axons and their future synaptic targets. As axons approach their target, they are instructed to slow down and remodel to form proper presynaptic terminals. Although significant progress has been made in the identification of the mechanisms that control axon guidance, little is known about the mechanisms that regulate the conversion of actively growing axon into a presynaptic terminal. We found that Wnt secreted proteins are retrograde signals that regulate the terminal arborization of axons and synaptic differentiation. Wnts released from postsynaptic neurons induce extensive remodelling on incoming axons. This remodelling is manifested by a decrease in axon extension with a concomitant increase in growth-cone size. This morphological change is correlated with changes in the dynamics and organization of microtubules. Studies of a vertebrate synapse and the Drosophila neuromuscular junction suggest that a conserved Wnt signalling pathway modulates presynaptic microtubules as axons remodel during synapse formation. In this paper I discuss the role of the Wnt–Dvl (Dishevelled protein)–GSK-3β (glycogen synthase kinase-3β) signalling pathway in axon remodelling during synapse formation in the central nervous system.

GSK3 takes centre stage more than 20 years after its discovery

2001 ◽  
Vol 359 (1) ◽  
pp. 1-16 ◽  
Author(s):  
Sheelagh FRAME ◽  
Philip COHEN
Keyword(s):  
Substrate Specificity ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
Glycogen Metabolism ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Dimensional Structure ◽  
Entire Body ◽  
Wnt Signalling Pathway ◽  
Wnt Proteins

Identified originally as a regulator of glycogen metabolism, glycogen synthase kinase-3 (GSK3) is now a well-established component of the Wnt signalling pathway, which is essential for setting up the entire body pattern during embryonic development. It may also play important roles in protein synthesis, cell proliferation, cell differentiation, microtubule dynamics and cell motility by phosphorylating initiation factors, components of the cell-division cycle, transcription factors and proteins involved in microtubule function and cell adhesion. Generation of the mouse knockout of GSK3β, as well as studies in neurons, also suggest an important role in apoptosis. The substrate specificity of GSK3 is unusual in that efficient phosphorylation of many of its substrates requires the presence of another phosphorylated residue optimally located four amino acids C-terminal to the site of GSK3 phosphorylation. Recent experiments, including the elucidation of its three-dimensional structure, have enhanced our understanding of the molecular basis for the unique substrate specificity of GSK3. Insulin and growth factors inhibit GSK3 by triggering its phosphorylation, turning the N-terminus into a pseudosubstrate inhibitor that competes for binding with the ‘priming phosphate’ of substrates. In contrast, Wnt proteins inhibit GSK3 in a completely different way, by disrupting a multiprotein complex comprising GSK3 and its substrates in the Wnt signalling pathway, which do not appear to require a ‘priming phosphate’. These latest findings have generated an enormous amount of interest in the development of drugs that inhibit GSK3 and which may have therapeutic potential for the treatment of diabetes, stroke and Alzheimer's disease.

Phillyrin ameliorates diabetic nephropathy through the PI3K/Akt/GSK-3β signalling pathway in streptozotocin-induced diabetic mice

2021 ◽  
pp. 096032712110515
Author(s):  
Tianyang Wang ◽  
Xuejiao Wen ◽  
Ziwen Zhang ◽  
Minjuan Xie ◽  
Jie Zhou
Keyword(s):  
Diabetic Nephropathy ◽  
Glycogen Synthase ◽  
Fasting Blood Glucose ◽  
Underlying Mechanism ◽  
Signalling Pathway ◽  
Chinese Herbs ◽  
Diabetic Patients ◽  
Haemoglobin A1c ◽  
Serum Blood Urea Nitrogen ◽  
Gsk 3Β

Diabetic nephropathy is a progressive kidney disease resulting from long-term hyperglycaemia in diabetic patients, and the underlying mechanism is complex and lacks effective treatments. Various active ingredients in Chinese herbs have been shown to alleviate renal injury and improve DN in recent years. Phillyrin, a natural medicinal active compound extracted from the Oleaceae family, has various pharmacological effects, including antioxidative, antiapoptotic and antiobesity effects. However, the role of phillyrin and its underlying mechanism in DN have not yet been explored. To investigate the effects of phillyrin on DN and its potential mechanisms of action, we performed experiments using streptozotocin (STZ)-induced DN mice as models. Phillyrin significantly reduced the levels of fasting blood glucose (FBG) and glycosylated haemoglobin A1c (HbA1c), downregulated the levels of serum blood urea nitrogen (BUN), serum creatinine (Scr), serum and urine β2-microglobulins (β2-MG) and improved the pathological changes of the kidney in a DN mouse model. Phillyrin also increased the level of antioxidants and attenuated oxidative damage in DN model mice. In addition, phillyrin inhibited Glycogen synthase kinase-3β (GSK-3β) activity by activating the PI3K/Akt signalling pathway, increased the Bcl-2/Bax ratio, reduced the release of cytochrome c from the mitochondria to the cytoplasm, subsequently inhibited the activation of caspase-3 and ultimately suppressed renal cell apoptosis. These findings suggested that phillyrin could be a new promising therapeutic strategy for DN, and this protective effect might be related to suppressing oxidative stress and apoptosis via the PI3K/Akt/GSK-3β pathway.

Alzheimer Disease and Related Tauopathies: Possible Neuroprotective Strategies

2018 ◽  
Vol 2 (3) ◽  
pp. 01-02
Author(s):  
Meketa Muñoz
Keyword(s):  
Alzheimer Disease ◽  
Glycogen Synthase ◽  
Vital Role ◽  
Current Therapy ◽  
Cyclin Dependent Kinase ◽  
Abnormal Hyperphosphorylation ◽  
Neuroprotective Strategies ◽  
Gsk 3Β ◽  
Cyclin Dependent Kinase 5

Alzheimer disease (AD) is the most common cause of dementia in adults. The current therapy for AD has only moderate efficacy in controlling symptoms, and it does not cure the disease. Recent studies have suggested that abnormal hyperphosphorylation of tau in the brain plays a vital role in the molecular pathogenesis of AD and in neurodegeneration. This article reviews the current advances in understanding of tau protein, regulation of tau phosphorylation, and the role of its abnormal hyperphosphorylation in neurofibrillary degeneration. Furthermore, several therapeutic strategies for treating AD on the basis of the important role of tau hyperphosphorylation in the pathogenesis of the disease are described. These strategies include (1) inhibition of glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (cdk5), and other tau kinases; (2) restoration of PP2A activity; and (3) targeting tau O-GlcNAcylation. Development of drugs on the basis of these strategies is likely to lead to disease-modifying therapies for AD.

scholarly journals Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1120 ◽  
Author(s):  
Manisha Gupte ◽  
Prachi Umbarkar ◽  
Anand Prakash Singh ◽  
Qinkun Zhang ◽  
Sultan Tousif ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Total Period ◽  
Gsk 3Β

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3βfl/flCre+/−) and controls (GSK-3βfl/flCre−/−) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients.

scholarly journals Overexpression of chloroplast-targeted ferrochelatase 1 results in a genomes uncoupled chloroplast-to-nucleus retrograde signalling phenotype

2020 ◽  
Vol 375 (1801) ◽  
pp. 20190401 ◽  
Author(s):  
Mike T. Page ◽  
Tania Garcia-Becerra ◽  
Alison G. Smith ◽  
Matthew J. Terry
Keyword(s):  
Gene Expression ◽  
Feedback Inhibition ◽  
Nuclear Gene ◽  
Signalling Pathway ◽  
Chloroplast Genes ◽  
Nuclear Gene Expression ◽  
Retrograde Signalling ◽  
Genes Encoding ◽  
Retrograde Signal

Chloroplast development requires communication between the progenitor plastids and the nucleus, where most of the genes encoding chloroplast proteins reside. Retrograde signals from the chloroplast to the nucleus control the expression of many of these genes, but the signalling pathway is poorly understood. Tetrapyrroles have been strongly implicated as mediators of this signal with the current hypothesis being that haem produced by the activity of ferrochelatase 1 (FC1) is required to promote nuclear gene expression. We have tested this hypothesis by overexpressing FC1 and specifically targeting it to either chloroplasts or mitochondria, two possible locations for this enzyme. Our results show that targeting of FC1 to chloroplasts results in increased expression of the nuclear-encoded chloroplast genes GUN4 , CA1 , HEMA1 , LHCB2.1, CHLH after treatment with Norflurazon (NF) and that this increase correlates to FC1 gene expression and haem production measured by feedback inhibition of protochlorophyllide synthesis. Targeting FC1 to mitochondria did not enhance the expression of nuclear-encoded chloroplast genes after NF treatment. The overexpression of FC1 also increased nuclear gene expression in the absence of NF treatment, demonstrating that this pathway is operational in the absence of a stress treatment. Our results therefore support the hypothesis that haem synthesis is a promotive chloroplast-to-nucleus retrograde signal. However, not all FC1 overexpression lines enhanced nuclear gene expression, suggesting there is still a lot we do not understand about the role of FC1 in this signalling pathway. This article is part of the theme issue ‘Retrograde signalling from endosymbiotic organelles’.

scholarly journals Altered Wnt signalling in the teenage suicide brain: focus on glycogen synthase kinase-3β and β-catenin

2013 ◽  
Vol 16 (5) ◽  
pp. 945-955 ◽  
Author(s):  
Xinguo Ren ◽  
Hooriyah S. Rizavi ◽  
Mansoor A. Khan ◽  
Yogesh Dwivedi ◽  
Ghanshyam N. Pandey
Keyword(s):  
Protein Expression ◽  
Glycogen Synthase ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Glycogen Synthase Kinase ◽  
Mrna Levels ◽  
Protein Levels ◽  
Wnt Signalling Pathway ◽  
Gsk 3Β ◽  
Teenage Suicide

Abstract Glycogen synthase kinase (GSK)-3β and β-catenin are important components of the Wnt signalling pathway, which is involved in numerous physiological functions such as cognition, brain development and cell survival. Their abnormalities have been implicated in mood disorders and schizophrenia. Teenage suicide is a major public health concern; however, very little is known about its neurobiology. In order to examine if abnormalities of GSK-3β and β-catenin are associated with teenage suicide, we determined the gene and protein expression of GSK-3β and β-catenin in the prefrontal cortex (PFC) and hippocampus obtained from 24 teenage suicide victims and 24 normal control subjects. Protein expression was determined using Western blot with specific antibodies and gene expression (mRNA levels) was determined using the real-time polymerase chain reaction method. No significant change was observed in the GSK-3β protein levels either in the PFC or hippocampus of suicide victims compared to controls. However, protein levels of pGSK-3β-ser9 were significantly decreased in the PFC and hippocampus of suicide victims compared to normal controls. We also found that GSK-3β mRNA levels were significantly decreased in the PFC but not in the hippocampus of teenage suicide victims compared to controls. Mean protein and mRNA levels of β-catenin were significantly decreased in both the PFC and hippocampus of teenage suicide group compared to controls. The observation that there is a decrease in β-catenin and pGSK-3β-ser9 in the PFC and hippocampus of teenage suicide victims does indicate a disturbance in the Wnt signalling pathway in teenage suicide.

scholarly journals The relationship of diabetes mellitus with Alzheimer’s disease: a literature review

2021 ◽  
Author(s):  
Fábio Dias Nogueira ◽  
Ana Klara Rodrigues Alves ◽  
Barbara Beatriz Lira da Silva ◽  
Ana Kamila Rodrigues Alves ◽  
Marlilia Moura Coelho Sousa ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Potential Link ◽  
The Central Nervous System ◽  
Gsk 3Β ◽  
Type 3 ◽  
The Brain

Introduction: Alzheimer’s disease (AD) is closely related to diabetes mellitus (DM), and AD is also considered to be type 3 diabetes (T3D). Glycogen synthase kinase-3β (GSK-3β) may be the potential link between DM and AD. GSK-3β is one of the main factors that lead to insulin deficiency and insulin resistance, and insulin resistance is a characteristic of the development of DM. In AD, GSK-3β plays an important role in hyperphosphorylation of the tau protein (tau) associated with microtubules, which is one of the pathological features in AD. Objective: To analyze DM as a factor for the development of AD. METHODOLOGY: This is an integrative review of the literature, which is a construction of a comprehensive analysis of the literature with pre-defined steps, carried out through PubMed, 1.501 articles were found, of which 10 were selected, through the simultaneous crossing between the descriptors “Diabetes mellitus”, “Alzheimer “. Articles written in Portuguese and English published between 2016 and 2021 were inserted. Results: DM associated with insulin resistance affects psychomotor efficiency, attention, learning memory, mental flexibility, speed and executive function of the brain, thus being an independent risk factor for cognitive impairment and damage to the central nervous system, hyperglycemia, which can cause increased oxidative stress leading to progressive functional and structural abnormalities in the brain. Conclusion:The risk of dementia in patients with DM is higher than in nondiabetic patients and it is also well known that DM2 / insulin resistance is involved in AD.

Recent Advances in the Discovery of GSK-3 Inhibitors from Synthetic Origin in the Treatment of Neurological Disorders

2021 ◽  
Vol 22 ◽  
Author(s):  
Supriyo Saha ◽  
Dilipkumar Pal ◽  
Satish Balasaheb Nimse
Keyword(s):  
Neurological Disorders ◽  
Synapse Formation ◽  
Homo Sapiens ◽  
Glycogen Synthase ◽  
Forced Swim Test ◽  
Bipolar Disorders ◽  
Tail Suspension Test ◽  
Adenosine Kinase ◽  
Cognitive Behaviour ◽  
Gsk 3Β

Background: Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase enzyme which controlled the neuronal functions such as neurite outgrowth, synapse formation, neurotransmission, and neurogenesis. The enzyme has two subunits as GSK-3α and GSK-3β. 4ACC, 1Q3D, 3AFG, 1UV5, 1Q5K are the important GSK-3 receptors isolated from Homo sapiens and Mus musculus. This enzyme mainly phosphorylates Tau protein with increased amount in neuronal fibres altogether with beta-amyloid plaques cause neuronal defects like Alzheimer, Parkinson’s and many more. Objective: We investigated the developments of various synthetic GSK-3 inhibitors responsible for the prevention and treatment of neurological disorders like Alzheimer disease, bipolar disorders, antidepressant, neuroprotective etc. Results and Conclusion: It was observed that structures of the GSK-3 inhibitors comprised of benzopyridine, benzthiazole, pyrazole, pyrazine, dioxolo-benzoxazin, oxadiazole, benzimidazole in the skeletal with cyclopropylamide, phenyl carbamothioate, 3-[(propan-2-yl)oxy]propan-1-amine in side chain. The molecules were evaluated against the effectivity of GSK-3, human adenosine kinase, cyclin dependent kinase, and phosphodiesterase-4 along with tail suspension test, forced swim test, percent neuronal survival and other cognitive behaviour. The observations confirmed the remarkable effects of the synthesized molecules to conquer Alzheimer, Parkinson’s depression, psychosis and other forms of neurological disorders.

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